Excess serum Na level in rats administered with high doses of (-)-epigallocatechin gallate-casein nanoparticles prepared with sodium caseinate.

(-)-Epigallocatechin gallate (EGCG)-incorporated casein nanoparticles benefit from excellent antioxidant, anti-inflammatory and anti-cancer activities due to their synergistic efficiency, but few studies have evaluated their safety. In this study, the EGCG-casein nanoparticles (EGCG-NPs) formulated using caseinate by ultrasonic treatment were evaluated for their subacute toxicity. The subacute toxicity test of EGCG-NPs through 28-day oral administration in rats did not exhibit adverse effect, with a no-observed-adverse-effect level (NOAEL) of at least 5.0 g per kg body weight (BW) per day, which was equivalent to 500 mg per kg BW EGCG per day. However, the serum Na level in females and males treated with 10.0 g per kg BW EGCG-NPs increased significantly as compared to the control rats (P < 0.05). Similar indications appeared in rats treated with 10.0 g per kg BW pure casein nanoparticles without EGCG, which indicated that high doses of caseinate nanoparticles result in an excess serum Na level. Therefore, we should consider the safety of the nanoparticle formulation of caseinate when it is used as a loading nutrient and a functional substance in foods.

Superior anti-infective potential of eugenol-casein nanoparticles combined with polyethylene glycol against Colletotrichum musae infections.

The aim of this study was to improve the stability of eugenol-casein nanoparticles (EL-CS-NPs) through polyethylene glycol (PEG) modification. The results show that modifying the EL-CS-NPs with PEG after loading with eugenol (EL) gives PEG-EL-CS-NPs, with increased stability. The NPs modified with higher-molecular-weight PEG showed better stability. A CS/PEG ratio of 200 : 1 (w/w) yielded the NPs with the best stability. A PEG20 K-EL-CS-NP dispersion remained stable in cold storage for over one year, and also exhibited stronger inhibitory effects against Colletotrichum musae inoculated on bananas than an EL-CS-NP dispersion, since it showed more prolonged sustained release of EL than the EL-CS-NP dispersion. Lyophilized PEG20 K-EL-CS-NP powder showed better effectiveness against mold on bread than lyophilized EL-CS-NPs powder. Using PEG to modify CS-NPs shows potential for improving the stability of CS-NPs loaded with hydrophobic substances for delivery in the fields of food and agriculture.

Magnetic Targeting and Ultrasound Activation of Liposome-Microbubble Conjugate for Enhanced Delivery of Anticancer Therapies.

Effective delivery of chemotherapeutics with minimal toxicity and maximal outcome is clinically important but technically challenging. Here, we synthesize a complex of doxorubicin (DOX)-loaded magneto-liposome (DOX-ML) microbubbles (DOX-ML-MBs) for magnetically responsive and ultrasonically sensitive delivery of anticancer therapies with enhanced efficiency. Citrate-stabilized iron oxide nanoparticles (MNs) of 6.8 ± 1.36 nm were synthesized, loaded with DOX in the core of oligolamellar vesicles of 172 ± 9.2 nm, and covalently conjugated with perfluorocarbon (PFC)-gas-loaded microbubbles to form DOX-ML-MBs of ∼4 µm. DOX-ML-MBs exhibited significant magnetism and were able to release chemotherapeutics and DOX-MLs instantly upon exposure to ultrasound (US) pulses. In vitro studies showed that DOX-ML-MBs in the presence of US pulses promoted apoptosis and were highly effective in killing both BxPc-3 and Panc02 pancreatic cancer cells even at a low dose. Significant reduction in the tumor volume was observed after intravenous administration of DOX-ML-MBs in comparison to the control group in a pancreatic cancer xenograft model of nude mice. Deeply penetrated iron oxide nanoparticles throughout the magnetically targeted tumor tissues in the presence of US stimulation were clearly observed. Our study demonstrated the potential of using DOX-ML-MBs for site-specific targeting and controlled drug release. It opens a new avenue for the treatment of pancreatic cancer and other tissue malignancies where precise delivery of therapeutics is necessary.

Engineered multifunctional biodegradable hybrid microparticles for paclitaxel delivery in cancer therapy.

Ovarian cancer is one of the most lethal gynecologic malignancies due to its rapid proliferation, frequent acquisition of chemoresistance, and widespread metastasis within the peritoneal cavity. Intraperitoneal (IP) chemotherapy has demonstrated significant anti-cancer potential but its broad clinical application is hindered by several drug delivery limitations. Herein, we engineer paclitaxel (PTX) laden hybrid microparticles (PTX-Hyb-MPs) for improved delivery of chemotherapy in ovarian cancer. The PTX-Hyb-MPs are comprised of a lipid-coated shell of poly (lactic acid-co-glycolic acid) (PLGA) encapsulating hydrophobic PTX. A co-axial electrohydrodynamic (CEH) process is used for one-step and scalable production of the PTX-Hyb-MP agent with controlled particles size, uniform size distribution, tunable thickness, and high encapsulation rate (92.17 ±â€¯6.9%). The multi-layered structure of the PTX-Hyb-MPs is verified by transmission electron microscopy and confocal fluorescence microscopy. The effect of lipid coating on the enhancement of particle interactions with cancer cells is studied by flow cytometry and confocal fluorescence microscopy. The anti-cancer effect of the PTX-Hyb-MPs is evaluated in SKOV-3 ovarian cancer cells in vitro and a cancer xenograft model in vivo, in comparison with conventional drug delivery methods. Our studies reveal that the PTX-Hyb-MP agent can be potentially used for locoregional treatment of ovarian cancer and other tissue malignancies with sustained drug release, tunable release profiles, enhanced drug uptake, and reduced systemic toxicity.

Sustained release paclitaxel-loaded core-shell-structured solid lipid microparticles for intraperitoneal chemotherapy of ovarian cancer.

The current clinical paradigm for ovarian cancer treatment has a poor prognosis, partially due to the efficacy and toxicity concerns associated with the available chemotherapeutic formulations. To overcome these limitations, we have designed core-shell-structured paclitaxel (PTX) laden solid lipid microparticles (PTX-SLMPs) for intraperitoneal treatment of ovarian cancer. A single-step coaxial electro hydrodynamic atomization (CEHDA) process has been explored to synthesize core-shell structure of PTX-SLMPs with the particle size of 1.76 ± 0.37 µm. Core-shell PTX-SLMPs have high encapsulation efficiency of 94.73% with sustained drug release profile. In vitro evaluation of PTX-SLMPs in SKOV-3 ovarian cancer cells yield significant enhancement in cytotoxicity when compared with Taxol®. In vivo pharmacokinetic study demonstrated slower absorption of PTX into the systemic circulation after intraperitoneal (i.p.) administration of PTX-SLMPs in Wistar rats implying the PTX-SLMPs remained in the peritoneal cavity and released the PTX for prolonged period of time. Through these studies, we have demonstrated the technical potential of core-shell structured PTX-SLMPs, which can enhance passive targeting of PTX to the tumor in the treatment of not only ovarian cancer but also in other peritoneal cancer.

Core-shell microencapsulation of curcumin in PLGA microparticles: programmed for application in ovarian cancer therapy.

In our study, we have established a novel liquid-driven co-flow focusing (LDCF) process to fabricate curcumin (CUR)-loaded poly (lactic-co-glycolic acid) (PLGA) microparticles (CPMs). LDCF-CPMs of size 20.26 ± 2.37 µm have high encapsulation efficiency (>70%) and were intended for application in ovarian cancer by intraperitoneal (IP) administration. LDCF-CPMs have smooth surface with narrow size distribution and a core-shell structured verified by confocal microscopy which can be precisely controlled by changing the flow rates of focusing, outer and inner phases. The LDCF-CPMs reveal the physiochemical stability with sustained release profile corresponding to 95% CUR release over a period of 14 days in an in vitro release medium. Moreover, LDCF-CPMs were testified for cytotoxicity against SKOV-3 ovarian cancer cell lines and peritoneal delivery advantages by animal experiments. The pharmacokinetics of LDCF-CPMs in rats following IP injection shows slow systemic absorption with mean residence time (MRT) of 13.54 h in comparison with 9.82 and 6.74 h for SE-CPMs and free CUR, respectively. In addition, IP delivery of CUR can expose the ovarian tumour to higher concentration for a longer duration by programming the thickness of the shell. The study provides compelling evidence for LDCF-CPMs having high therapeutic opportunity in the treatment of peritoneal cancers, such as ovarian, that reside in the peritoneal cavity.

Characteristics of Artemether-Loaded Poly(lactic-co-glycolic) Acid Microparticles Fabricated by Coaxial Electrospray: Validation of Enhanced Encapsulation Efficiency and Bioavailability.

Artemether is one of the most effective drugs for the treatment of chloroquine-resistant and Plasmodium falciparum strains of malaria. However, its therapeutic potency is hindered by its poor bioavailability. To overcome this limitation, we have encapsulated artemether in poly(lactic-co-glycolic) acid (PLGA) core-shell microparticles (MPs) using the coaxial electrospray method. With optimized process parameters including liquid flow rates and applied electric voltages, experiments are systematically carried out to generate a stable cone-jet mode to produce artemether-loaded PLGA-MPs with an average size of 2 µm, an encapsulation efficiency of 78 ± 5.6%, and a loading efficiency of 11.7%. The in vitro release study demonstrates the sustained release of artemether from the core-shell structure in comparison with that of plain artemether and that of MPs produced by single-axial electrospray without any relevant cytotoxicity. The in vivo studies are performed to evaluate the pharmacokinetic characteristics of the artemether-loaded PLGA-MPs. Our study implies that artemether can be effectively encapsulated in a protective shell of PLGA for controlled release kinetics and enhanced oral bioavailability.

Microfluidic fabrication of stimuli-responsive microdroplets for acoustic and optical droplet vaporization.

A droplet-based microfluidic flow-focusing system was developed for on-chip fabrication of stimuli-responsive microdroplets (SRMs) that underwent rapid liquid-to-gas phase transition and volume expansion upon external stimuli. Silver nanoparticles (SNPs) were suspended in perfluorocarbon (PFC) liquid and encapsulated in a lipid shell to form a SRM. The SRM size can be well controlled from 4 µm to 50 µm by adjusting the flow rates of the inner and the outer liquid phases. The acoustic and the optical droplet vaporization processes of the SRMs were demonstrated in benchtop experiments. Upon acoustic stimulation by a therapeutic ultrasound transducer at 1 MHz and 1 W cm-2, the SRMs were activated and the induced echogenicity was monitored by clinical ultrasonography. Upon optical stimulation by a 445 nm laser beam at power intensity larger than 35 W cm-2, the SRMs were activated and the volume expansion of the SRMs was monitored by bright field microscopy. Our benchtop experiments demonstrated the technical feasibility for acoustic and optical mediation of the SRMs. The technique can be potentially used for multiple therapeutic applications such as thermal ablation, vascular occlusion, and locoregional drug delivery.